Skip to main content
SpringerLink
Log in

Continuous enteral protease inhibition as a novel treatment for experimental trauma/hemorrhagic shock

  • Original Article
  • Published:
European Journal of Trauma and Emergency Surgery Aims and scope Submit manuscript

Abstract

Purpose

Trauma and hemorrhagic shock (T/HS) is a major cause of morbidity and mortality. Existing treatment options are largely limited to source control and fluid and blood repletion. Previously, we have shown that enteral protease inhibition improves outcomes in experimental models of T/HS by protecting the gut from malperfusion and ischemia. However, enteral protease inhibition was achieved invasively, by laparotomy and direct injection of tranexamic acid (TXA) into the small intestine. In this study, we tested a minimally invasive method of enteral protease inhibitor infusion in experimental T/HS that can be readily adapted for clinical use.

Methods

Wistar rats were exsanguinated to a mean arterial blood pressure (MABP) of 40 mmHg, with laparotomy to induce trauma. Hypovolemia was maintained for 120 min and was followed by reperfusion of shed blood. Animals were monitored for an additional 120 min. A modified orogastric multi-lumen tube was developed to enable rapid enteral infusion of a protease inhibitor solution while simultaneously mitigating risk of reflux aspiration into the airways. The catheter was used to deliver TXA (T/HS + TXA) or vehicle (T/HS) continuously into the proximal small intestine, starting 20 min into the ischemic period.

Results

Rats treated with enteral protease inhibition (T/HS + TXA) displayed improved outcomes compared to control animals (T/HS), including significantly improved MABP (p = 0.022) and lactate (p = 0.044). Mass spectrometry-based analysis of the plasma peptidome after T/HS indicated mitigation of systemic proteolysis in T/HS + TXA.

Conclusion

Minimally invasive, continuous enteral protease inhibitor delivery improves outcomes in T/HS and is readily translatable to the clinical arena.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and materials

The datasets analyzed for this study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Abbreviations

T/HS:

Trauma/hemorrhagic shock

TXA:

Tranexamic acid

T/HS + TXA:

Trauma/hemorrhagic shock with enteral tranexamic acid (experimental group)

MABP:

Mean arterial blood pressure

HYPVOL:

Hypovolemia (experimental period following blood withdrawal)

REPERF:

Reperfusion (experimental period following resuscitation)

WBC:

White blood cells

References

  1. Institute of Medicine Committee on Injury Prevention and Control: Reducing the burden of injury: advancing prevention and treatment. Washington: National Academy Press, 1999.

  2. Sakran JV, Greer SE, Werlin E, McCunn M. Care of the injured worldwide: trauma still the neglected disease of modern society. Scand J Trauma Resusc Emerg Med. 2012;15(20):64.

    Article  Google Scholar 

  3. Rhee P, Joseph B, Pandit V, Aziz H, Vercruysse G, Kulvatunyou N, Friese RS. Increasing trauma deaths in the United States. Ann Surg. 2014;260(1):13–21.

    Article  Google Scholar 

  4. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23–32.

    Article  CAS  Google Scholar 

  5. Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096–101.

    Article  CAS  Google Scholar 

  6. CRASH-2 collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019; 394(10210):1713–23.

  7. Cai J, Ribkoff J, Olson S, Raghunathan V, Al-Samkari H, DeLoughery TG, Shatzel JJ. The many roles of tranexamic acid: an overview of the clinical indications for TXA in medical and surgical patients. Eur J Haematol. 2020;104(2):79–87.

    Article  CAS  Google Scholar 

  8. Aletti F, Maffioli E, Negri A, Santamaria MH, DeLano FA, Kistler EB, Schmid-Schönbein GW, Tedeschi G. Peptidomic analysis of rat plasma: proteolysis in hemorrhagic shock. Shock. 2016;45(5):540–54.

    Article  CAS  Google Scholar 

  9. Bauzá-Martinez J, Aletti F, Pinto BB, Ribas V, Odena MA, Diaz R, et al. Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality. Br J Anaesth. 2018;121(5):1065–74.

    Article  Google Scholar 

  10. Penn AH, Hugli TE, Schmid-Schönbein GW. Pancreatic enzymes generate cytotoxic mediators in the intestine. Shock. 2007;27(3):296–304.

    Article  CAS  Google Scholar 

  11. Kistler EB, Alsaigh T, Chang M, Schmid-Schonbein GW. Impaired small-bowel barrier integrity in the presence of lumenal pancreatic digestive enzymes leads to circulatory shock. Shock. 2012;38:262–7.

    Article  CAS  Google Scholar 

  12. Chang M, Alsaigh T, Kistler EB, Schmid-Schonbein GW. Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine. PLoS ONE. 2012;7:e40087.

    Article  CAS  Google Scholar 

  13. DeLano FA, Schmid-Schönbein GW. Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock. Shock. 2014;41(1):55–61.

    Article  CAS  Google Scholar 

  14. Alsaigh T, Chang M, Richter M, Mazor R, Kistler EB. In vivo analysis of intestinal permeability following hemorrhagic shock. World J Crit Care Med. 2015;4:287–95.

    Article  Google Scholar 

  15. Altshuler AE, Kistler EB, Schmid-Schonbein GW. Autodigestion: Proteolytic degradation and multiple organ failure in shock. Shock. 2016;45:483–9.

    Article  CAS  Google Scholar 

  16. DeLano FA, Hoyt DB, Schmid-Schonbein GW. Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci Transl Med. 2013;5:169.

    Article  Google Scholar 

  17. Santamaria M, Aletti F, Li JB, Tan A, Chang M, Leon J, Schmid-Schönbein GW, Kistler EB. Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock. J Trauma Acute Care Surg. 2017;83(2):263–70.

    Article  CAS  Google Scholar 

  18. Aletti F, Santamaria M, Chin K, Mazor R, Kistler EB. Enteral tranexamic acid decreases proteolytic activity in the heart in acute experimental hemorrhagic shock. J Cardiovasc Pharmacol Ther. 2019;24(5):484–93.

    Article  CAS  Google Scholar 

  19. WO2017184843—Enteral Drug Delivery System.

  20. DeLegge MH. Aspiration pneumonia: incidence, mortality, and at-risk populations. JPEN J Parenter Enteral Nutr. 2002;26(6):S19-24.

    Article  Google Scholar 

  21. Gomes GF, Pisani JC, Macedo ED, Campos AC. The nasogastric feeding tube as a risk factor for aspiration and aspiration pneumonia. Curr Opin Clin Nutr Metab Care. 2003;6(3):327–33.

    PubMed  Google Scholar 

  22. Blumenstein I, Shastri YM, Stein J. Gastroenteric tube feeding: techniques, problems and solutions. World J Gastroenterol. 2014;20(26):8505–24.

    Article  Google Scholar 

  23. Kagan I, Hellerman-Itzhaki M, Neuman I, Glass YD, Singer P. Reflux events detected by multichannel bioimpedance smart feeding tube during high flow nasal cannula oxygen therapy and enteral feeding: First case report. J Crit Care. 2020;60:226–9.

    Article  CAS  Google Scholar 

  24. Gimenes FRE, Baracioli FFLR, Medeiros AP, Prado PRD, Koepp J, Pereira MCA, Travisani CB, Rabeh SAN, Souza FB, Miasso AI. Factors associated with mechanical device-related complications in tube fed patients: A multicenter prospective cohort study. PLoS ONE. 2020;15(11):e0241849.

    Article  CAS  Google Scholar 

  25. Torsy T, Saman R, Boeykens K, Duysburgh I, Van Damme N, Beeckman D. Comparison of two methods for estimating the tip position of a nasogastric feeding tube: a randomized controlled trial. Nutr Clin Pract. 2018;33(6):843–50.

    Article  Google Scholar 

  26. Ritter LS, McDonagh PF. Low-flow reperfusion after myocardial ischemia enhances leukocyte accumulation in coronary microcirculation. Am J Physiol. 1997;273(3 Pt 2):H1154–65.

    CAS  PubMed  Google Scholar 

  27. Ritter LS, Orozco JA, Coull BM, McDonagh PF, Rosenblum WI. Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke. Stroke. 2000;31(5):1153–61.

    Article  CAS  Google Scholar 

  28. Corso CO, Okamoto S, Rüttinger D, Messmer K. Hypertonic saline dextran attenuates leukocyte accumulation in the liver after hemorrhagic shock and resuscitation. J Trauma. 1999;46(3):417–23.

    Article  CAS  Google Scholar 

  29. Canale P, Squadrito F, Altavilla D, Ioculano M, Zingarelli B, Campo GM, Urna G, Sardella A, Squadrito G, Caputi AP. TCV-309, a novel platelet activating factor antagonist, inhibits leukocyte accumulation and protects against splanchnic artery occlusion shock. Agents Actions. 1994;42(3–4):128–34.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Department of Defense award W81XWH-17-2-0047 (EBK); ‘ShockOmics’ grant #602706, 7th Framework Program of the European Union (GWSS, GT); CelSys Shock” Marie Curie International Outgoing Fellowship PIOF-GA-2012-328796, 7th Framework Program of the European Union (FA). We thank Dr. Rafi Mazor for assistance with the interpretation of the histological images, and Dr. Fernando dos Santos for the critical appraisal of the discussion of the results.

Funding

Department of Defense award W81XWH-17–2-0047 (EBK); ‘ShockOmics’ grant #602706, 7th Framework Program of the European Union (GWSS, GTW); CelSys Shock” Marie Curie International Outgoing Fellowship PIOF-GA-2012–328796, 7th Framework Program of the European Union (FA).

Author information

Authors and Affiliations

  1. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

    Federico Aletti, Frank A. DeLano, Hao Mu & Geert W. Schmid-Schönbein

  2. Department of Veterinary Medicine, University of Milano, Milan, Italy

    Elisa Maffioli & Gabriella Tedeschi

  3. Cimaina, University of Milano, Milan, Italy

    Elisa Maffioli & Gabriella Tedeschi

  4. Department of Anesthesiology & Critical Care, University of California San Diego, La Jolla, CA, USA

    Erik B. Kistler

  5. Department of Anesthesiology & Critical Care, VA San Diego Healthcare System, San Diego, CA, USA

    Erik B. Kistler

Authors
  1. Federico Aletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank A. DeLano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisa Maffioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geert W. Schmid-Schönbein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gabriella Tedeschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erik B. Kistler
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

FA: study design; animal experiments; data analysis; histological preparations; conception, design, realization and testing of the multilumen catheter; results discussion and interpretation; manuscript draft. FAD: animal experiments; conception of the histological preparations; design and realization of the multilumen catheter; manuscript revision and approval. EM: execution of the peptidomics experiments; peptidomics data analysis, discussion and interpretation; manuscript revision and approval. HM: histological preparations and analysis; manuscript revision and approval. GWSS: study design; design of the multilumen catheter; results discussion and interpretation; manuscript revision and approval. GT: design of the peptidomics experiments; eptidomics data discussion and interpretation; manuscript revision and approval. EKB: study design; critical appraisal of the clinical translational potential of the continuous enteral infusion method; results discussion and interpretation; manuscript revision and approval.

Corresponding author

Correspondence to Federico Aletti.

Ethics declarations

Ethics approval

The animal protocol was reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (protocol number S15117) and conforms to the Guide for the Care and Use of Laboratory Animals, 8th edition, by the National Institutes of Health (2011).

Conflict of interests

FAD and GWSS own stock in Inflammagen Inc., a company that develops new shock treatments.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aletti, F., DeLano, F.A., Maffioli, E. et al. Continuous enteral protease inhibition as a novel treatment for experimental trauma/hemorrhagic shock. Eur J Trauma Emerg Surg 48, 1579–1588 (2022). https://doi.org/10.1007/s00068-020-01591-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00068-020-01591-y

Keywords

Search

Navigation